A unique sustained-release drug delivery system, Time-Controlled Explosion System (TCES), was described in U.S. Pat. No. 4,871,549 issued Nov. 3, 1989 to Ueda et al. Drug release is caused by explosion of an insoluble, water permeable membrane after a definite period of time. Beads or granules contain the drug and a swelling agent enclosed by the water insoluble membrane. Water permeates the membrane and causes the swelling agent to expand until the internal forces on the membrane cause it to burst or explode, thereby releasing the drug. This mechanism is especially useful with water insoluble drugs in which those prior art delay mechanisms related to diffusion of the drug through a permeable coating would not be effective.
A remarkable feature of the TCES is that drug is not released from the completely coated pellets or spheres until the membrane bursts, and then it is all available. This can provide for a pulse of drug release. The lag time before release is related to the thickness of the membrane with maximum lag times of approximately four hours reported by Ueda.
One of the principal uses for delayed release forms of medication is to provide for a once a day oral administration that releases drug in a continuous controlled rate or in a series of sequential pulses throughout the 24 hour period. This ensures a reasonably uniform blood level for maximum efficacy with the least toxic effect from high peaks of blood concentration. This is not easily accomplished with the system of Ueda because the insoluble membrane must be made very thick for long delays,and this makes explosion less reliable. If the membrane never bursts, the drug will be lost in the stool and the patient will get less drug than prescribed and never be aware of it. Furthermore, in cases where there is a delayed stomach emptying time, much of the explosion may take place in the stomach and not be available for absorbtion until the pyloric sphincter opens. This may present a very large dose for sudden absorbtion that may be very dangerous. Furthermore, acid unstable drugs should not be released to the acidic stomach contents, where an indeterminate portion of the drug dose may be destroyed.